Field of the Invention
This invention relates to novel imidazole 5-position substituted angiotensin II antagonists. The invention also relates to pharmaceutical compositions containing these novel imidazoles and pharmaceutical methods using them, alone and in conjugation with other drugs, especially diuretics, angiotensin converting enzyme (ACE) inhibitors, and non-steroidal anti-inflammatory drugs (NSAIDS).
The compounds of this invention inhibit the action of the hormone angiotensin II (All) and am useful therefore in alleviating angiotensin induced hypertension. The enzyme renin acts on a blood plasma a2-globulin, angiotensinogen, to produce angiotensin I, which is then converted by ACE to All. The latter substance is a powerful vasopressor agent which has been implicated as a causative agent for producing high blood pressure in various mammalian species, such as the rat, dog, and man. The compounds of this invention inhibit the action of All at its receptors on target cells and thus prevent the increase in blood pressure produced by this hormone-receptor interaction. By administering a compound of this invention to a species of mammal with hypertension due to All, the blood pressure is reduced. Administration of a compound of this invention with a diuretic such as furosemide or hydrochlorothiazide, either as a stepwise combined therapy (diuretic first) or as a physical mixture, enhances the antihypertensive effect of the compound. Administration of a compound of this invention with a NSAID can prevent renal failure which sometimes results from administration of a NSAID.
Several peptide analogs of All are known to inhibit the effects of this hormone by competitively blocking the receptors, but their experimental and clinical applications have been limited by their partial agonist activity and lack of oral absorption (M. Antonaccio, Clin. Exp. Hypertens., 1982, A4, 27-46; D. H. P. Streeten and G. H. Anderson, Jr.--Handbook of Hypertension, Clinical Pharmacology of Antihypertensive Drugs, ed., A. E. Doyle, Vol. 5, pages 246-271, Elsevier Science Publisher, Amsterdam, The Netherlands, 1984).
Several non-peptide antagonists of angiotensin II, including some biphenylmethyl imidazoles, have been disclosed. U.S. Pat. Nos. 5,137,902 and 5,138,069 disclose biphenylmethylimidazoles (A) where R.sup.1 may be a ##STR2## phenyl substituted in the 2'-position with acidic functional groups, such as carboxy and tetrazole, and where imidazole substitutent R.sup.7 may be alkyl or optionally substituted phenyl, and where R.sup.8 may be formyl, acyl, carboxy, alkoxycarbonyl, aminocarbonyl, alkoxyalkyl and hydroxyalkyl. U.S. Applications Ser. No. 90/03683 and Ser. No. 07/545302 disclose substituted imidazoles of the same basic structure where R.sup.7 may be optionally substituted aryl or heteroaryl. European Application EP401,030 (Merck) describes imidazoles of structure (B), where Q represents various nitrogenous functional groups, T may be carboxy, alkoxycarbonyl or aminocarbonyl, r may be 1, (X)q can represent a single bend, R.sup.6 (B).sub.p may represent alkyl and R.sup.1 may be SO.sub.2 NHR.sup.9, SO.sub.2 NH-heteroaryl, SO.sub.2 NHCOR.sup.25 or SO.sub.2 NHCONHR.sup.25, where R.sup.9 is H, alkyl, phenyl or benzyl, and where R.sup.25 is aryl, heteroaryl, cycloalkyl or optionally substituted alkyl.
Australian Application AU-A-80163/91 (EP465,368, Roussel-Uclaf) discloses substituted imidazoles (C) where R.sup.1 may be alkyl, m may be 1, either R.sup.2 or R.sup.3 is OR.sup.4, or a sulfurous group of structure --S(O).sub.n R.sup.4, ##STR3## --SO(R.sup.4).dbd.NS(O).sub.n X' or --SSR.sup.4, where R.sup.4 represents a variety of optionally substituted alkyl, alkenyl, alkynyl, acyl or nitrogenous or sulfurous radicals. The imidazole nitrogen substituent (CH.sub.2).sub.m -Y may represent a biphenylmethyl group, which may be substituted in the 2'-position by acidic groups, such as --(CH.sub.2).sub.m1 --S(O).sub.m2 -X-R.sup.10, in which m1 may be 0-4, m2 may be 0-2, X may be a single bond, --NH--, --NH--CO--, or --NH--CO--NH-- and R.sup.10 is an optionally substituted alkyl, alkenyl, aryl or heteroaryl radical. European Application EP479,479 (Merck) discloses biphenylmethyl imidazoles (D) where R.sup.1 B may represent alkyl, R.sup.3 may be H, alkyl, alkenyl or alkynyl, perfluoroalkyl, halogen, --NO.sub.2, --CN or optionally substituted phenyl, R.sup.4 includes formyl, acyl, carboxy, alkoxycarbonyl, aminocarbonyl, alkoxyalkyl and hydroxyalkyl, X may be a single bond, and R.sup.5 includes --SO.sub.2 NH-heteroaryl, --SO.sub.2 NHCOR.sup.12 and --SO.sub.2 NHCONR.sup.2 R.sup.12, in which R.sup.2 is H or alkyl, and R.sup.12 is aryl, heteroaryl, cycloalkyl, perfluoroalkyl or optionally substituted C1-C4 alkyl, where the alkyl substituents include aryl, heteroaryl, alkyl, OH, SH, alkoxy, thioalkoxy, halo, carboxy, alkoxycarbonyl, --NO.sub.2, optionally substituted amino and various phosphoryl radicals. ##STR4##
European patent application number EPA 503, 162, (published Sep. 16, 1992, Hoechst Aktiengesellschaft) describes compounds of structure (E) wherein Z can be nitrogen, and X and Y are independently CR.sup.2. R.sup.1 can be alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, or benzyl. R.sup.2 can be H, halogen, nitro perfluoroalkyl, pentafluorophenyl, cyano, phenyl, phenylalkyl, alkyl, alkenyl, phenylalkenyl, imidazolylalkyl, triazolylalkyl, tetrazolylalkyl, ethers, esters, thioethers, sulfides, sulfoxides, sulfones, amides and other groups as well. L-(O)q-A may represent a biphenylmethyl group which may be substituted in the 2' position with an acidic radical. ##STR5##
None of the above publications disclose the imidazole biphenylsulfonyl carbamates of the present invention. It is well known that two types of angiotensin II receptors are widely distributed in various mammalian tissues (P. C. Wong et al., Cardiovascular Drug Reviews 1991; 9:. 317-339; Trends in Endoctocrinol. Metab. 1992; 3: 211-217). The angiotensin II receptor most directly involved in the mediation of blood pressure is termed the AT.sub.1 receptor, and is characterized by high sensitivity to the non-peptide antagonist DuP 753. A second angiotensin II receptor, designated AT.sub.2, is sensitive to another class of non-peptide All antagonists, represented by PD 123177 (ibid.), and to the peptide CGP42112A. Angiotensin II has approximately equal affinity for both receptor subtypes.
Recent evidence suggests that the AT.sub.2 receptor may have a role in mediating the synthesis and breakdown of cardiac connective tissues. For example, Matsubara et ##STR6## al. (The FASEB Journal 6, 4: A941, 1992) have reported that PD123177, but not DuP 753, blocks the All-stimulated inhibition of collagenase in cultured cardiac fibroblasts. Both PD123177 and DuP 753 are reported by Zhou et al. to block the All-stimulated increase in collagen synthesis in cardiac fibroblasts (The FASEB Journal 6, 4: A1914, 1992).
Tsutsumi and Saavedra have found AT.sub.2 receptors in cerebral arteries (Am. J. Physiol. 261: H667-H670, 1991). An analog of PD123177, PD123319, has been reported by Brix and Haberl (The FASEB Journal 6, 4: A1264, 1992) to block the pial artery dilation induced by angiotensin II in a rat cranial window preparation monitored by intravital microscopy. This suggests that the AT.sub.2 receptor may have a role in modifying cerebral blood flow.
The AT.sub.2 selective antagonist CGP42112A has been reported by LeNoble et al. (The FASEB Journal 6, 4: A937, 1992) to block the increase in microvascular density induced by angiotensin II in the chick chorioallantoic membrane, suggesting that angiotensin II may in some contexts mediate angiogenesis through AT.sub.2 receptors.
As noted above, DuP 753, disclosed in U.S. Pat. No. 5,138,069, is a selective AT.sub.1 antagonist, having extremely low affinity for the AT.sub.2 receptor. No data is presented in U.S. Pat. No. 5,138,069 or the other references above which suggests that any of the compounds disclosed possess high AT.sub.2 affinity.
In addition to potent AT.sub.1 antagonist and antihypertensive properties, the imidazole compounds of the present invention possess potent AT.sub.2 antagonist properties. Since AT.sub.1 antagonism leads to increased levels of circulating angiotensin II in vivo (Y. Christen et al., Am. J. Hypertension, 1991; 4: 350S-353S), and the AT.sub.2 -mediated consequences, if any, of higher All levels are unknown, simultaneous AT.sub.1 /AT.sub.2 antagonism may prove desirable during AT.sub.1 -targeted therapy.